More women use tobacco during pregnancy than any other substance, yet little is known about the effects of on early human development. Prenatal tobacco exposure is the single largest preventable risk factor for low birth weight and prematurity, resulting in increased healthcare costs. Nicotine acts on the developing fetal nervous system directly through effects on neurotransmitter systems and indirectly by vasoconstriction of placental blood flow. In animals, prenatal nicotine exposure prematurely signals cell differentiation by altered dopamine and acetylcholine activity that results in disrupted cell development, reduced cell number, and aberrant synaptic connections, with particularly marked effects on dopaminergic systems. Because dopaminergic systems are related to motor, attention, and temperament behavior in infants, children, and adults, these behaviors are particularly susceptible to disruption by prenatal tobacco exposure. Because of the vulnerable nervous system, the added risk of prenatal tobacco exposure in preterm infants may be doubly deleterious. Alternatively, preterm birth typically shortens the duration of in utero exposure in the third trimester, with attenuated prenatal tobacco exposure effects. Finally, specific gene variants that result in net reductions in dopaminergic activity may render these infants more vulnerable to prenatal tobacco exposure effects. This study will examine the effects of prenatal tobacco exposure as a function of perinatal risk and genetic vulnerability, while accounting for the social environment. A large sample of preterm and full term infants (n = 360) will be recruited (with oversampling on prematurity and exposure level) and carefully selected on background characteristics to maximize tobacco exposure-related differences. Thorough maternal interviews and biochemical analysis of cotinine level (maternal and infant urine, infant meconium) will be used to measure prenatal tobacco exposure. Postnatal tobacco exposure, in addition to alcohol, caffeine, and other substance exposure, also will be measured through similarly thorough multi-methods. Neonatal outcome will be assessed longitudinally to more reliably determine effects on early development; both in the hospital where the effects of postnatal exposure and social environment are minimized, and after discharge where these effects are more prominent. Multiple methods are used to assess different neonatal outcome domains, with instruments that capture age-dependent neurobehavioral skill and physical growth. Sophisticated statistical methods will uncover prenatal tobacco exposure effects on developmental processes, including level and growth rates.